Kidney cancer in the Middle East and North Africa region: a 30-year analysis (1990–2019)

Kidney cancer, a type of urogenital cancer, imposes a high burden on patients. Despite this, no recent research has evaluated the burden of this type of cancer in the Middle East and North Africa (MENA) region. This study explored the burden of kidney cancer from 1990 to 2019 according to age, sex and socio-demographic index (SDI). The Global Burden of Disease (GBD) 2019 data was utilized to estimate the incidence, death, and disability-adjusted life-years (DALYs) caused by kidney cancer. These estimates were reported as counts and as age-standardised rates with 95% uncertainty intervals (UIs). The estimated age-standardised incidence, mortality, and DALY rates of kidney cancer in 2019 were 3.2 (2.8–3.6), 1.4 (1.2–1.6), and 37.2 (32.0–42.6) per 100,000, respectively. Over the period from 1990 to 2019, these rates have increased by 98.0%, 48.9%, and 37.7%, respectively. In 2019, the United Arab Emirates, Qatar, and Lebanon had the largest age-standardised incidence, mortality, and DALY rates. The smallest age-standardised incidence rates were seen in Yemen, Afghanistan, and the Syrian Arab Republic. Additionally, the smallest age-standardised mortality and DALY rates were observed in the Syrian Arab Republic, Yemen, and Morocco. The highest incidence rates were found among individuals aged 75–79 in both males and females. In 2019, the MENA/Global DALY ratio exceeded one for females aged 5–19 age and males aged 5–14, compared to 1990age groups in males. The burden of kidney cancer consistently rose with increasing SDI levels from 1990 to 2019. The increasing burden of kidney cancer highlights the urgent need for interventions aimed at improving early diagnosis and treatment in the region.


Estimation framework
Kidney cancer was classified using the International Classification of Diseases, version 10 (ICD10), which included the following codes C64-C64.2,C64.4-C64.6,C64.8-C64.9,C65-C65.2,C65.9, D30.0-D30.1, and D41.0-D41.1 10 .The vital registration, verbal autopsy, and cancer registry data were used to obtain the cause of death database and transformed them into estimates of mortality using the mortality-to-incidence ratios 12 .The cause-of-death ensemble model (CODEm) was created utilising these mortality estimates and data sourced from the cancer registries and vital registration system 12 .CODEm was used to model mortality for all locations that had sparse or no available data, and the covariates used to model kidney cancer have been previously reported 12 .The CoDCorrect algorithm was applied to correct the aggregated number of predicted single-cause death estimates in each age-sex-state-year group.Following this, the mortality estimates were divided by the mortality-toincidence ratio, in order to estimate the incidence of kidney cancer 12 .In order to model the 10-year prevalence of kidney cancer, the survival of each incidence cohort was modelled using the mortality-to-incidence ratio as a scalar.This approach positioned each nation on a spectrum from the theoretical best to the worst survival rates.Impairment was measured by separating the overall prevalence into the four different stages: diagnosis and primary treatment, controlled, metastatic, and terminal 12 .The diagnostic and primary therapy phase spans from the commencement of symptoms to the cessation of treatment.After the treatment has finished the controlled phase starts, which in turn finishes after one of the following occurs: cure (recurrence-and progression free survival after 10 years); death from another cause; or moving to the metastatic phase.
Table S1 shows the disability weights for the four sequelae.Any patients who survived longer than ten years were considered cured and classified into either the diagnosis and primary treatment phase or the controlled phase.The durations of the three different phases were as follows: diagnosis and primary therapy (5.3 months), metastatic phase (5.38 months), and the terminal phase (1 month) 10,12 .

Severity and years lived with disability
Sequela-specific years lived with disability (YLDs) were modelled by multiplying the sequela-specific prevalence rates with their respective disability weights.The lay descriptions of each sequelae and their disability weights have previously been reported 10,12 .The YLD and years of life lost (YLL) were added together to estimate the DALYs attributable to kidney cancer.All estimates were standardized using the GBD standard population 10,12 and had 95% confidence intervals (UIs).The 95% confidence intervals were produced by running 1000 draws at each stage of the modelling process, and included the 25th and 975th values of the ordered draws.The relationship SDI has with the burden of kidney cancer was investigated utilizing smoothing splines 13 .The SDI ranges from 0 (least developed) to 1 (most developed), was estimated by combining the fertility rate among those younger than 25, average number of years in education for individuals older than 15, and the mean income (smoothed over the prior decade).The figures were made using R (Version 3.5.2). 100,000 (4.9 to 9.4), and Lebanon, with 5.5 (4.1 to 7.4).Conversely, the smallest rates were found in Yemen [1.4 (0.9 to 1.9)], Afghanistan [1.5 (1.0 to 2.1)], and the Syrian Arab Republic [1.5 (1.1 to 2.1)] (Table S2). Figure 1A provides a detailed visualization of the age-standardised incidence rates of the disease for each country in 2019, highlighting the considerable disparities across the region.
In 2019, the age-standardised DALY rate of kidney cancer varied between 17.7 and 123.7 cases per 100,000 across the countries in the region.The largest rates were observed in the United Arab Emirates [123.7 (47.1 to 197.5)], Qatar [72.8 (50.0 to 100.2)], and Lebanon [56.6 (42.1 to 76.9)], while the lowest were in the Syrian Arab Republic [17.7 (12.5 to 24.0)], Yemen [20.4 (13.4 to 29.3)], and Morocco [22.7 (16.6 to 28.8)] (Table S4). Figure 1C shows the age-standardised DALY rates of kidney cancer for each sex in 2019.
The age-standardised death rate of the disease was markedly higher in 2019 compared to 1990 in nine of the countries, with no significant changes in the rest.Saudi Arabia [124.4% (43.1 to 332.9)], Sudan [107.4% (31.0 to 184.1)], and Oman [101.6% (28.8 to 239.3)] experienced the most substantial increases in the age-standardised death rates (Fig. S2 and Table S3).
The age-standardised DALY rate of kidney cancer was higher in 2019 than in 1990 in eight of the countries, with no significant changes in the remainder.The largest increases were observed in Saudi Arabia [118.9% (41.0 to 299.5)], Sudan [83.2% (11.5 to 161.1)], and Oman [80.3% (11.9 to 188.2)] (Fig. S3 and Table S4).

Age and sex patterns
In 2019, the incidence rate for both sexes exhibited a notable decline with age up to those aged 10-14, remained stable up to the 25-29 age range, and then dramatically increased to the 75-79 age range, before decreasing up to those aged 95 + .The total number of incident cases of kidney cancer showed a similar pattern: it decreased with age up to the 15-19 age range for both males and females, then increased to the 60-64 age range and then declined to the 95 + age range.In 2019, the incident cases of the disease were higher in females up to the age of 44, after which the incidence rate was higher among men (Fig. 2A).
The mortality rate of kidney cancer in 2019 remained stable for both sexes in the 1-34 age range, and then rose with age.Furthermore, in 2019 the regional number of deaths due to kidney cancer decline up to the 15-19 age range, increased to the 65-69 age range, and then declined with age.Additionally, the number of deaths and the death rate were generally lower in women (Fig. 2B).
In 2019, the DALY rate of kidney cancer in the MENA region decreased up to the 10-14 age range for both sexes, remained unchanged up to the 25-29 age range, rose dramatically to the 65-69 age range and then declined to the 95 + age range.Also in 2019, the total number of DALYs in the MENA region decreased for both males and females up to the 15-19 age range, then increased up to the 55-59 age range and then declined to the 95 + age range.Overall, the number of DALYs and the DALY rate were again higher among males (Fig. 2C).
The DALY rate in 2019 was below the global DALY rate (ratio of MENA/Global DALY rate < 1) for males of most ages, except for those in the 5-19 age range.Specifically, the DALY rate in MENA was higher for males in the 5-14 age range, but was similar for those aged 15-19.For females, the MENA/Global DALY ratio in 2019 was higher among those aged 5-19, similar in the 1-4, 20-24, and 30-39 age ranges and lower in the other age ranges.When comparing 1990 to 2019, the MENA/Global DALY ratios for males were larger for all ages, except for the 1-19 range (lower) and the 25-29 range (similar).For females, the MENA/Global DALY ratios increased in all age groups between 1990 and 2019, except for the 25-29 and the 95 + age ranges, which were similar (Fig. 3).

Relationship with the Socio-demographic Index (SDI)
From 1990 to 2019, the age-standardised DALY rate of kidney cancer showed a consistent upward trend with increases in the SDI.Notably, several countries experienced a larger than expected age-standardised DALY rate, including the United Arab Emirates, Qatar, Afghanistan, Palestine, Iraq, Libya, and Lebanon.Conversely, Morocco, Tunisia, Kuwait, Yemen, Jordan, Oman, Algeria, Saudi Arabia, Egypt, and the Syrian Arab Republic were lower than anticipated (Fig. 4).

Discussion
Our findings revealed that in 2019, the age-standardised incidence, death and DALY rates for kidney cancer were 3.2, 1.4 and 37.2, respectively.Additionally, these rates all significantly increased from 1990 to 2019.The data also indicated that both mortality and morbidity were higher among men, as well as among middle-aged and elderly populations.Furthermore, there was a clear positive correlation between a nation's level of socioeconomic development and its burden of kidney cancer.This suggests that as countries progress socioeconomically, the burden of kidney cancer also escalates, potentially due to factors such as lifestyle changes, increased life expectancy, and improved diagnostic capabilities.
In 2017, the global age-standardized rates for kidney cancer were 4.9 per 100,000 for incidence (95% UI: 4.7-5.1),1.7 per 100,000 for mortality (95% UI: 1.6-1.8)and 41.1 per 100,000 for DALYs (95% UI: 38.7-42.5) 8.In contrast, the present study reported corresponding figures of 3.2, 1.4 and 37.2, respectively.These findings incidence rate of kidney cancer in this region was notably higher among men compared to women 8 , but in 2019 this gender disparity had diminished.The highest number of deaths occurred among those aged 65-69, with an overall increase in mortality across all age ranges.Consistent with global trends, the death rate remained higher among males than females in the MENA region, as was also the case in 2017 8 .Previous studies have indicated that as countries become more developed, the incidence of kidney cancer increases.The highest incidence rates have been observed in North America and Eastern Europe, with European countries also exhibiting the highest death rates 8,14 .The current research demonstrated that the level of sociodemographic development plays a substantial role in the age-standardized DALY rate of kidney cancer in the population.The countries with high SDI levels (i.e., Kuwait, Bahrain, Saudi Arabia, and the United Arab  www.nature.com/scientificreports/Emirates) all had above average burdens.Although the overall burden of kidney cancer tends to rise with higher SDI levels, the relationship is not strictly linear.A global study also reported a slight increase up to an SDI of about 0.3, followed by a larger rise that peaked at its highest slope between 0.5 and 0.7, before decreasing again 8 .There are several plausible reasons why higher SDI countries experience a greater burden of kidney cancer.One significant factor is the utilisation of advanced diagnostic techniques, which include magnetic resonance imaging, ultrasonography, and computed tomography.These technologies, predominantly available in high SDI and high-income countries, can lead to overdiagnosis.This increased detection capability may contribute to the higher reported incidence of kidney cancer in these regions 15 .
Previous studies have also identified hypertension as a potent risk factor for kidney cancer 16,17 .In a 2021 study by Mills et al., it was found that the prevalence of hypertension in MENA was less than 28% among men, marking the lowest prevalence rate worldwide 18 .In addition, its prevalence in women was 28-29.9%,which was also low compared to other regions in the world 18 .It should be noted that compared to 1975, systolic blood pressure has increased by 0-2 mmHg on average for men and decreased by more than 2 mmHg for women, which may be associated with the lower deaths and DALYs found in women 18 .The research by Mills et al., also found a global increase in the absolute burden of hypertension for both sexes between 2000 and 2010, except in MENA where the absolute burden in women slightly decreased 19 .Therefore, the lower incidence of kidney cancer in the MENA region, especially among women, may be attributable to the lower prevalence of hypertension in the region.However, it may be that the poor diagnostic policies and limited facilities in the MENA region has led to underestimating the prevalence of both hypertension and kidney cancer.
A high body mass index (BMI) and obesity are other risk factors for kidney cancer.A cohort study by Ga Eun Nam, involving 23.3 million East Asians, showed a positive correlation between BMI, waist circumference and the chances of developing kidney cancer 20 .This indicates that obesity could potentially be a risk factor for the disease 20 .In the 2016 report by the World Health Organization, they reported that obesity is more common in the MENA region than in other areas 21 .In countries such as the United Emirates, Jordan, Iraq, Egypt, Turkey, Saudi Arabia, and Libya the prevalence of obesity has been estimated to exceed 30% 21,22 .This suggests that the region has a higher prevalence of obesity than many other regions.Therefore, the relatively low rate of kidney cancer observed in the present study appears to be inconsistent with the high prevalence of obesity in this region.
Smoking is a predisposing factor for RCC 23,24 .Thus, we can expect a higher rate of kidney cancer in regions with higher smoking.In 2020, the global prevalence of smoking was estimated to be 32.6% for males and 6.5% females, resulting in 7.0 million deaths 25 .Furthermore, between 1990 and 2020 there was a 27.2% decrease in the prevalence of smoking among men and a 37.9% decrease among females 25 .This decline was larger among high-income nations, than it was in low-income countries 25 .More specifically, high income countries saw a decline of over 40% in smoking rates, while the decline was significantly smaller in most low-and middle-income countries 25 .Consequently, the higher incidences of kidney cancer in countries with higher SDI levels do not align well with the larger declines in smoking prevalence observed in these high SDI countries.In addition, the global decline in smoking and the global increase in kidney cancer are incompatible with the fact that smoking substantially contributes to kidney cancer.Furthermore, kidney cancer is more common in men who smoke more than among women.These statistics cannot rule out the adverse effect of smoking on kidney health, but they appear to attenuate the importance of smoking's impact, when compared to other risk factors.In contrast, from 1990 until the present the MENA region has had a lower prevalence of smoking than globally, so a part of lower kidney cancer rate may be attributable to this fact 25 .
There is accumulating evidence to suggest several new risk factors (e.g., alcohol consumption, low physical activity, and high parity among women) could play a role in kidney cancer 17 .At present, the available evidence is not sufficient to prove the abovementioned factors are causally related to kidney cancer 17 .Males are considerably more at risk of developing kidney cancer and tend to experience poorer outcomes compared to women.Differences in the occupational risk factors, genetics-based variations, sex hormones, and tumor characteristics all contribute to this finding.However, further research is needed in whether sex is an independent prognostic factor for kidney cancer risk 26 .A Swedish case-control study revealed that multi-parity increases the RCC cancer risk by up to 1.42 times, compared to nulliparous females 27 .Furthermore, in the Canadian cohort study parous females were found to be 1.78 times higher risk of having kidney cancer, when compared to nulliparous women 26 .Physiological and hormonal changes during pregnancy result in elevated estrogen levels, increased renal hyperfiltration, and weight gain.Each of these factors independently contributes to the risk of kidney cancer, thereby explaining the observed correlation between parity and the incidence of the disease 26 .The low risk of kidney cancer in females, which increases following pregnancy, would appear to indicate that sex hormones are involved, but this needs further investigation.
Alcohol consumption differs worldwide, ranging from the lowest consumption in MENA (< 1 L per capita annually) to the highest consumption in Central and Eastern Europe (> 12 L per capita) 28 .The global consumption of alcohol has risen from 5.9 L per capita in 1990 to 6.5 L in 2017 28 , which may be associated with renal cancers 29,30 , but further investigation into this issue is needed.

Strengths and limitations
This research offers the most current data regarding the burden of kidney cancer in MENA, providing valuable insights for health policymakers.However, several limitations must be acknowledged when reading these results.Firstly, there is a possibility that the burden of kidney cancer in MENA may have been underestimated.This potential underestimation is due to sparse data and the fact that there are no comprehensive cancer registries in most of the MENA countries, especially in the low-or middle-income nations.Secondly, the study did not differentiate the burden of kidney cancer by histological type or by race/ethnicity, despite the significant sociocultural variation in this region.This lack of granularity may obscure important variations in the disease's

Figure 3 .
Figure 3. Ratio of the Middle East and North Africa region's DALY rate to global DALY rate of kidney cancer by age group and sex, 1990-2019.DALY = disability-adjusted-life-years.(Generated from data available from http:// ghdx.healt hdata.org/ gbd-resul ts-tool).

Figure 4 .
Figure 4. Age-standardised DALY rates of kidney cancer for the 21 MENA countries in 2019, by SDI; Expected values based on the Socio-demographic Index and disease rates in all locations are shown as the black line.Each point shows the observed age-standardised DALY rate for each country in 2019.DALY = disability-adjustedlife-years.SDI = Socio-demographic Index (Generated from data available from http:// ghdx.healt hdata.org/ gbdresul ts-tool).